The functions of FE65 proteins and their roles in dementias of the Alzheimer type

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Dementias of the Alzheimer type (DAT) are human neurodegenerative diseases that debilitate millions of elderly people, presenting enormous financial and emotional burdens worldwide. Its pathogenesis involves the beta-amyloid precursor protein (betaPP), the aberrant processing or functioning of which results in amyloid plaques, the hallmark of DAT pathology. Attempts to decipher their normal function and metabolism of betaPP have focused on the interacting proteins. A particularly strong interactor, the FE65 protein, has properties of an adaptor protein. An understanding of its functions may elucidate the molecular mechanisms underlying the pathogenesis of DAT.This thesis focuses on the functions of FE65 and its role in DAT. Using a gene-targeting approach, FE65 was disrupted in transgenic mice. These mice were bred with a line of transgenic mice (Tg2576) that overexpress a mutant form of betaPP, resulting in extensive deficits of beta amyloid.After documenting the successful targeting of FE65, a Western analysis of FE65 protein expression was carried out with a panel of FE65-specific antibodies. These demonstrated that the 97 kDa full-length FE65 (p97) was ablated in the mutant mice while a previously undescribed FE65 isoform with apparent molecular mass of 60 kDa (p60) was expressed in both wild type and mutant mice. p60 has a truncated N-terminus, and is likely to be generated through alternative translation. Expressions of the two isoforms appeared to be brain-region distinct, and age-dependent. The mutant mice were viable, and showed no obvious physical impairments or histopathological abnormalities. However, homozygous (p97FE65-/-) and heterozygous (p97FE65+/-) mutant mice exhibited poorer performances than wild type mice on a passive avoidance task when tested at 14 months. p97FE65-/- mice at 14 months also exhibit impaired hidden-platform acquisition and a severe reversal-learning deficit, but normal visual-platform acquisition in the Morris water maze tests. Probe trials confirmed impairments in p97FE65-/- mice in re-learning of new spatial information, suggesting a hippocampal-dependent memory extinction deficit. Reduced secretion of Abeta peptides was observed in primary neuronal cultures of hybrid mice (p97FE65-/-/Tg2576).These studies suggest an important and novel function of FE65 in learning and memory.